Eva Tomiak

Breast-Cancer Risk in Families with Mutations in PALB2

BACKGROUND Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P<0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. (Funded by the European Research Council and others.).

A Meta-Analysis of the Neuropsychological Effects of Adjuvant Chemotherapy Treatment in Women Treated for Breast Cancer

ABSTRACT Given the improvement in mortality rates associated with breast cancer, the importance of understanding the long-term neuropsychological consequences of chemotherapy is becoming increasingly vital. This study applies meta-analytic techniques to the scant literature on the relationship between contemporary adjuvant chemotherapy treatment for breast cancer and cognitive dysfunction as examined through neuropsychological indices. Seven studies (involving more than 300 participants) were selected from over 200 potential articles, based on three inclusion criteria: presence of breast cancer, administration of chemotherapy treatment, and use of neuropsychological tests. From these, nine treatment-control comparisons were used to generate 129 Hedges d effect sizes across the cognitive domains of simple attention, working memory short- and long-term memory, speed of processing, language, spatial abilities, and motor function. Small to medium cumulative effect sizes, showing diminished cognitive function for chemotherapy treatment groups compared to control groups, were obtained for each of the eight cognitive domains. Overall, these results suggest that women who undergo adjuvant chemotherapy as treatment for breast cancer may experience subtle yet consequential cognitive decline.

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Oral Etoposide and Carboplatin: Effective Therapy for Elderly Patients with Small Cell Lung Cancer

PurposeElderly patients with small cell lung cancer (SCLC) and/or those with comorbid conditions are frequently not considered candidates for standard combination chemotherapy. An active, but less toxic regimen is needed for this group of patients. Patients and MethodsForty-seven elderly (>65 years) or medically unfit patients with SCLC were treated with oral etoposide 100 mg/m2 × 7 days and carboplatin 150 mg/m2 day 1. Treatment was given every 3–4 weeks for six cycles in responding patients. Patients responding to the chemotherapy regimen were also treated with prophylactic cranial irradiation, and limited-stage patients received thoracic radiotherapy. The study population included 36 extensive-stage patients and 11 limited-disease patients with renal or cardiac disease that precluded standard chemotherapy. The median age of the study population was 69 years (range: 47–84). ResultsNine of 47 patients were inevaluable for response, including four patients who succumbed to sepsis. Of the 38 patients evaluable for response, 71% responded (95% CI: 56–86%) (88% LD; 67% ED) with a complete response in 29% of patients (50% LD; 23% ED). Based on an analysis of intent to treat, the overall response rate was 60% and the median survival time of the whole group was 46 weeks (LD, 59 weeks; ED, 45 weeks). Treatment was generally well tolerated. Neutropenia was the dose-limiting toxicity; the median nadir granulocyte count was 1.04 × 109/L (range: 0–8.2). ConclusionWe conclude that this regimen can provide palliation to SCLC patients who might not otherwise be considered for systemic chemotherapy.

The lived experience of hope among parents of a child with Duchenne muscular dystrophy: perceiving the human being beyond the illness

Objectives: Duchenne muscular dystrophy (DMD) is genetically determined, progressive and incurable. Our studys primary objective was to describe the lived experience of hope among parents of a child with DMD. Methods: Semi-structured interviews were conducted with 12 parents having a child with DMD. A qualitative/ phenomenological approach was utilized to analyse the essential aspects of this experience. Results: We show that the experience of parental hope emerges from the cognitive appraisal of DMD. The childs illness can be perceived in three ways: as a severe loss, a call to adapt or a way to rediscover the child. Each of these appraisals leads to different ways of hoping. Parents can hope for a cure, the childs well-being or to see their child becoming a whole person. Hope can help parents absorb the initial crisis, sustain their adaptation or prepare for the fatal outcome. Discussion: Previous research has demonstrated that cognitive appraisal plays a central role in psychosocial adaptation to illness. Our research indicates that perception can also shape the nature of hope and suggests that health professionals should pay particular attention to the nature of parental hope. The fabric of parental hope can give an indication of how parents are coping and adjusting.

Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families

Background:Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families.Methods:The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions.Results:We identified one previously reported deleterious mutation, p.Arg186* (c.556C>T), and two novel variants; missense substitution p.Cys119Arg and an intronic variant c.83-26A>G. p.Arg186* segregated with the disease in the family and two ovarian carcinomas available for analysis showed loss of the wild-type allele, but the novel variants are likely neutral.Conclusion:RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.

The role of chemotherapy in invasive thymoma: a review of the literature and considerations for future clinical trials

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. I I. I?. 13. Background and natural history Prognostic factors . . . . . . . ..__ _ _.__.._ Surgery and radiotherapy in the treatment of invasive thymoma Potential role for chemotherapy in the treatment of invasive thymoma Single agent chemotherapy in invasive thymoma . . Combination chemotherapy for thymoma Combined modality therapy for invasive thymoma . Toxicity of chemotherapy in patients with thymoma . Future directions . . . . . . . . .._._.._...._...._._..._._......_... Acknowledgements . . . . . . . . . . . . . . . . .._._......._ _._...._.._ Biographies . . . . . . . . . . . . . . . . . . .._._._ _._.._......._._..._ Reviewer . . . . . . . . . . . . . . . . . . . . .._._._._ _ _.._. References . . . . . . . . . . . . . . . . . .._ _.__.__... .,

DICER1 mutations in an adolescent with cervical embryonal rhabdomyosarcoma (cERMS)

To the Editor: Embryonal rhabdomyosarcomas of the cervix (cERMS) (“cervical sarcoma botryoides”) are rare embryonal tumors, usually diagnosed in childhood or adolescence, with a world literature of uterine/cervical ERMS limited to 115 cases [1]. The association of cERMSwith germlineDICER1mutations was first established in three families by Foulkes in 2011, and subsequently reported by Dehner et al., although the coexistence of cERMS and ovarian Sertoli-Leydig cell tumors (OSLCT) had previously been recognized [2–4]. In 2012, Doros et al. [5] reported germline DICER1 mutations in 2/52 (3.8%) sporadic ERMS, including 7 uterine/vaginal/pelvic cases.

Paclitaxel plus hydroxyurea as second line therapy for non-small cell lung cancer

We tested paclitaxel (Taxol) and low dose hydroxyurea as second line therapy in 30 patients with non-small cell lung cancer since both drugs are active against non-small cell lung cancer in other settings, and since hydroxyurea may reverse chemotherapy resistance by disrupting double minute chromosomes. Hydroxyurea 500 mg was given orally each Monday, Wednesday, Friday starting 1 week before paclitaxel, and continuing until removal from study. Paclitaxel 135 mg/m2 was given i.v. over > or = 1 h every 3 weeks with dexamethasone, diphenhydramine, and ranitidine. Patients could have paclitaxel doses escalated to 175 mg/m2 in course 2 and to 200 mg/m2 in course 3, where tolerated. Sixteen males and 14 females were treated. All patients had previously received a single cisplatin-based chemotherapy regimen and 23 had previously received radiotherapy. Twelve patients had adenocarcinomas, six had squamous cell carcinomas, and 12 had large cell carcinomas. Eight patients had Stage IIIb cancers and 22 had Stage IV. Paclitaxel doses were 135 mg/m2 in 56 courses, 175 mg/m2 in 24, and 200 mg/m2 in 15. Treatment was well tolerated. Median granulocyte nadirs were 2.5 (x 10(9)/l) for paclitaxel 135 mg/m2, 1.8 for 175 mg/m2, and 1.3 for 200 mg/m2. No patient developed febrile neutropenia, and none required a dose reduction. Two patients had reversible anaphylaxis. Other toxicities were quite tolerable. They included fatigue, myalgias, dizziness, paresthesias, diarrhea, alopecia, mucositis, flushing, headache, swollen red hands, and anxiety. One patient had a partial remission and 15 had stable disease (including six with minor responses). Median survival was 20 (95% CI, 12-34) weeks, with 19% of patients remaining alive at 1 year from initiation of treatment. This is a well-tolerated regimen with modest activity as second line chemotherapy for patients with non-small cell lung cancer previously treated with cisplatin regimens. Higher doses would be feasible and other strategies are now being explored.

Phase II study of a one hour paclitaxel infusion in combination with carboplatin for advanced non-small cell lung cancer

PURPOSE To determine the activity, toxicity, and optimal dose of paclitaxel when given by one hour infusion combined with carboplatin in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty-seven previously untreated patients with stage IIIB or IV NSCLC were enrolled. Paclitaxel was administered by one hour infusion at a dose of 175 mg/m2 for the first cycle, and was escalated up to 255 mg/m2 over successive cycles if tolerated. In the absence of toxicity, the carboplatin dose was kept constant at an area under the concentration-time curve (AUC) of 6. Cycles were repeated at 3-week intervals until progression or intolerable toxicity occurred. RESULTS Thirty-six patients were evaluable for toxicity and survival, and thirty-five for responses. The partial response rate was 10 of 35 (29%) and there were no complete responses. The median duration of response was 4.8 months (range 0.5-11.7 months). The median survival duration was 6.5 months, and 1 year survival was 31%. The mean paclitaxel dose was 188 mg/m2. Treatment was generally well tolerated. Four patients (11%) had febrile neutropenia. Five patients (14%) had grade 3 neuropathy, and 4 (11%) had grade 3 nausea and vomiting. Minor toxicities included alopecia, myalgias, arthralgias and stomatitis. CONCLUSIONS Paclitaxel and carboplatin is a well-tolerated regimen that can safely be given by a one hour paclitaxel infusion. The modest response rate observed in this study may be due to either the low dose-intensity of paclitaxel or the short infusion duration. Further trials to optimize the relative doses of paclitaxel and carboplatin are needed.